With advent of HAART, life expectancy for HIV-infected patients has greatly increased, making HIV disease a chronic illness. Consequently, a number of slowly developing side effects of HIV infection are becoming apparent and constitute a significant clinical problem. Many of these co-morbidities, such as cardiovascular disease, dyslipidemia, and metabolic syndrome, are caused by virus- and anti-HIV treatment-mediated impairment of normal metabolism of cholesterol. Importantly, metabolic changes occur not only in HIV-infected cells, which are relatively few in HAART-treated subjects, but also in uninfected cells and tissues. Our studies performed in both in vitro and in vivo models of HIV infection have established that HIV protein Nef released from infected cells impairs activity of cholesterol transporter ABCA1 and interferes with ABCA1-dependent cholesterol efflux in uninfected cells. These effects of extracellular Nef on uninfected tissues may be responsible for metabolic co-morbidities (atherosclerosis, dyslipidemia, diabetes) in HIV-infected patients. However, the mechanism of cholesterol metabolism impairment induced by extracellular Nef and the contribution of this impairment to metabolic complications of HIV infection are not fully understood. This project will address these questions by pursuing the following Specific Aims: 1) To determine how extracellular Nef affects cholesterol metabolism in uninfected cells; 2) To characterize metabolic effects of extracellular Nef; 3) To test the anti-pathogenic effect of drugs targeting cholesterol metabolism. Proposed studies are highly significant as they address pathogenesis of HIV-associated metabolic complications, a leading co-morbidity in HIV disease. This proposal has a significant translational component, as in Aim 3 we will investigate a new therapeutic strategy to treat HIV infection and its metabolic complications using drugs affecting lipid metabolism. The proposal utilizes the expertise of two co-PIs, who have a long history of successful collaboration and complementary expertise in HIV virology (Dr. Bukrinsky) and cholesterol metabolism (Dr. Sviridov).